title: Heterosubtypic cross-protection induced by whole inactivated influenza virus vaccine in mice: influence of the route of vaccine administration.
abstract: BACKGROUND
  Development of influenza vaccines capable of inducing broad protection against different virus subtypes is necessary given the ever-changing viral genetic landscape. Previously, we showed that vaccination with whole inactivated virus (WIV) induces heterosubtypic protection against lethal virus infection in mice. Whole inactivated virus-induced cross-protection was found to be mediated primarily by flu-specific CD8+ T cells.
  
  
  OBJECTIVE
  As it has been demonstrated that the route of vaccine administration strongly influences both the quantity and quality of vaccine-induced immunity, in this study, we determined which route of WIV administration induces optimal heterosubtypic cross-protection.
  
  
  METHODS
  We compared the magnitude of the immune response and heterosubtypic protection against lethal A/PR/8/34 (H1N1) infection after subcutaneous (SC), intramuscular (IM), and intranasal (IN) vaccination with A/NIBRG-14 (H5N1) WIV.
  
  
  RESULTS
  Subcutaneous and IM administration was superior to IN administration of influenza WIV in terms of flu-specific CD8+ T-cell induction and protection of mice against lethal heterosubtypic challenge. Surprisingly, despite the very low flu-specific CD8+ T-cell responses detected in IN-vaccinated mice, these animals were partially protected, most likely due to cross-reactive IgA antibodies.
  
  
  CONCLUSIONS
  The results of this study show that the magnitude of WIV-induced flu-specific CD8+ T-cell activity depends on the applied vaccination route. We conclude that parenteral administration of WIV vaccine, in particular IM injection, is superior to IN vaccine delivery for the induction of heterosubtypic cross-protection and generally appears to elicit stronger immune responses than mucosal vaccination with WIV.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Natalija
authors.initials: N
authors.lastname: Budimir
authors.forename: Aalzen
authors.initials: A
authors.lastname: de Haan
authors.forename: Tjarko
authors.initials: T
authors.lastname: Meijerhof
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Anke
authors.initials: A
authors.lastname: Huckriede
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D056738:Cross Protection; D004195:Disease Models, Animal; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D014611:Vaccination / Q000379:methods*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D007252:Influenza Vaccines; D015164:Vaccines, Inactivated
keywords: Cross-protection; cytotoxic T lymphocytes; influenza; mucosal vaccination; parenteral vaccination; whole inactivated virus